Acute pain alerts an organism to danger and is crucial to its survival. In contrast, chronic pain arising from pathological functioning of sensory pathways is often debilitating to those afflicted. Voltage-gated calcium channels (VGCCs) are central to both short- and long- term pain mechanisms; they provide a source of calcium influx that alters sensory neuron excitability, exocytosis and gene transcription. G proteins (which inhibit sensory neuron calcium channels) and RGS proteins (which terminate G protein inhibition) together provide dynamic regulation of calcium influx through VGCCs. Such regulation is essential to sensory neuron function and plasticity. My work will focus specifically on the mechanisms and physiological importance of RGS3 in sensory neurons. Preliminary data demonstrates that RGS3 activity is stimulated directly by calcium influx through VGCCs, providing an activity-dependent mechanism to terminate G protein signaling and sustain calcium influx in the active cells. I will use site directed mutagenesis to identify domains in RGS3 important for its calcium-dependent action (Aim 1) and electrophysiological recording to explore calcium-dependent RGS3 activation in native cells under normal physiological conditions (Aim 2). Such information may, in the long term, lead to new strategies to treat chronic pain.